American Journal of Pathology

Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. We aimed to investigate whether Ficolin-A influences NET formation through pyroptosis to exacerbate lipopolysaccharides (LPS)-induced lung injury. The expression of Ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were employed to elucidate regulatory mechanisms. Pearson's correlation coefficient was utilized to analyze the correlation between Ficolins and pyroptosis- and NET-related markers in clinical samples...

Tumor necrosis factor alpha-induced protein 8 (TIPE/TNFAIP8/OXi-α) family are a newly discovered series of proteins involved in immune regulation and tumorigenesis. TIPE1, as the member of TIPE/TNFAIP8/OXi-α family, has emerged as an anti-cancer drug target as it is promotes cancer cell apoptosis and inhibits cell proliferation. Here, the current study aimed to systematically reveal that TIPE1 regulates the activity of protein arginine methyltransferase 1 (PRMT1) and the subsequent methylation of signal transducer and activator of transcription 3 (STAT3) to suppress oral squamous cell carcinoma (OSCC) growth...

No abstract text is available yet for this article.

Radiation-induced enteritis, a significant concern in abdominal radiation therapy, is closely associated with gut microbiota dysbiosis. The critical mucus layer plays a pivotal role in preventing the translocation of commensal and pathogenic microbes. While the significant expression of REGγ in intestinal epithelial cells is well established, its role in modulating mucus layer and gut microbiota remains enigmatic. Current study revealed notable changes in gut microorganisms and metabolites in irradiated mice lacking REGγ, as opposed to wild-type mice...

Low-grade chronic inflammation contributes to both aging and the pathogenesis of age-related diseases. White adipose tissue (WAT) in obese individuals exhibits chronic inflammation, which is associated with obesity-related disorders. Aging exacerbates obesity-related inflammation in WAT; however, the molecular mechanisms underlying chronic inflammation and its exacerbation by aging remain unclear. Age-related decline in activity of the proteasome, a multi-subunit proteolytic complex, has been implicated in age-related diseases...

Cholestatic liver diseases encompass a range of organic damages, metabolic disorders, and dysfunctions within the hepatobiliary system, arising from various pathogenic causes. These factors contribute to disruptions in bile production, secretion, and excretion. Cholestatic liver diseases can be classified into intrahepatic and extrahepatic cholestasis according to the location of occurrence. The etiology of cholestatic liver diseases are complex, which include drugs, poisons, viruses, parasites, bacteria, autoimmune responses, tumors and genetic metabolism...

Ferroptosis is a new form of cell death characterized by iron-dependent lipid peroxidation. Whether ferroptosis is involved in retinal microvascular dysfunction under diabetic condition is not known. The expression of ferroptosis related genes in patients with proliferative diabetic retinopathy (PDR) and in diabetic mice was determined with RT-qPCR. Reactive oxygen species (ROS), iron content, lipid peroxidation products, and ferroptosis-associated proteins in the cultured human retinal microvascular endothelial cells (HRMECs) and in the retina of diabetic mice were examined...

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, while mucosal healing is critical for remission. Serine is a non-essential amino acid that supports epithelial and immune cell metabolism and proliferation, however, whether these roles impact IBD pathogenesis is not well understood. Here, we show that serine synthesis increases selectively in the epithelial cells of colons from patients with IBD and murine models of colitis...

This study was designed to discern the effect of heavy scavenger metallothionein on glutathione (GSH) deprivation-evoked cardiac anomalies and mechanisms involved with an emphasis on ferroptosis. WT and cardiac metallothionein transgenic mice received GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mM in drinking water) for 14 days prior to assessment of myocardial morphology and function. BSO evoked cardiac remodeling and contractile anomalies including cardiac hypertrophy, interstitial fibrosis, enlarged left ventricular chambers, deranged ejection fraction, fraction shortening, cardiomyocyte contractile capacity, intracellular Ca2+ handling, sarcoplasmic reticulum Ca2+ reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis and apoptosis...

Genetic polymorphisms that impair VLDL secretion are linked to hepatic steatosis, fibrosis and hepatocellular cancer (HCC). Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO X Fabp1 null (Fabp1/Mttp DKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKO mice on HCC incidence and progression in comparison to Fabp1/Mttp DKO mice. DEN treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared to flox controls, while diethylnitrosamine (DEN)- treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks...

Polycystic ovary syndrome is a highly heterogenous and genetically complex endocrine disorder. Although the etiology remains mostly elusive, growing evidences suggested abnormal changes of DNA methylation correlate well with systemic and tissue-specific dysfunctions in polycystic ovary syndrome. Dehydroepiandrosterone-induced polycystic ovary syndrome-like mouse model was generated, which has similar metabolic and reproductive phenotype as human polycystic ovary syndrome patients, and used to experimentally validate potential role of aberrant DNA methylation in polycystic ovary syndrome in this study...

Nearly 70% of preterm deliveries occur spontaneously, and the clinical pathways involved include preterm labor (PTL) and preterm premature rupture of membranes (pPROM). Prediction of preterm delivery is considered crucial due to the significant effects of preterm birth on health and the economy at both the personal and community levels. Although similar inflammatory processes occur in both term and preterm delivery, the premature activation of these processes or exaggerated inflammatory response triggered by infection or sterile factors leads to preterm delivery...

Changes in the anterior segment due to type 2 diabetes mellitus (T2DM) are not well characterized, in part due to the lack of a reliable animal model. This study evaluates changes in the anterior segment, including crystalline lens health, corneal endothelial cell density, aqueous humor metabolites and ciliary body vasculature, in a rat model of type 2 diabetes mellitus (T2DM) compared with human eyes. Sprague-Dawley male rats were fed a high fat diet (HFD, 45% fat) or normal diet, and HFD rats were injected intraperitoneally with streptozotocin (STZ) to create a model of T2DM...

Hyaluronan (HA), a negatively charged linear glycosaminoglycan, is a key macromolecular component of the articular cartilage extracellular matrix. The differential effects of HA are determined by a spatially/temporally regulated display of HA receptors, such as CD44 and Receptor for Hyaluronan Mediated Motility (RHAMM). HA signaling through CD44 with RHAMM has been shown to stimulate inflammation and fibrotic processes. This study shows an increased expression of RHAMM in pro-inflammatory macrophages. Interfering with HA/RHAMM interactions using a 15mer RHAMM-mimetic, HA binding peptide (P15-1) together with high molecular weight (HMW)HA reduced the expression and release of inflammatory markers and increased the expression of anti-inflammatory markers in pro-inflammatory macrophages...

α-Synuclein (α-Syn) is a key determinator of Parkinson disease (PD) pathology, but synapse and microcircuit pathologies in the retina underlying visual dysfunction are poorly understood. Using the old transgenic M83 PD model (mice aged 16 to 18 months) coupled with histochemical and ultrastructural analyses and ophthalmologic measurements, we revealed that abnormal α-Syn aggregation in the outer plexiform layer (OPL) was associated with degeneration in the CtBP2+ ribbon synapses of photoreceptor terminals and protein kinase Cα+ rod bipolar cell terminals, whereas α-Syn aggregates in the inner retina correlated with the reduction and degeneration of tyrosine hydroxylase- and parvalbumin-positive amacrine cells...

25% of cervical cancers are classified as endocervical adenocarcinomas (EACs), which comprise a highly heterogeneous group of tumors. A histopathological risk stratification system known as the Silva pattern system was developed based on morphology. However, accurately classifying such patterns can be challenging. The objective was to develop a deep learning pipeline (Silva3-AI) that automatically analyzes whole-slide-image-based histopathological images and identifies Silva patterns with high accuracy. Initially, a total of 202 patients with EACs and histopathological slides were obtained from QLHSDU for developing and internally testing the Silva3-AI model...

No abstract text is available yet for this article.

Corneal nerve impairment contributes significantly to dry eye disease (DED) symptoms and is thought to be secondary to corneal epithelial damage. Transient receptor potential vanilloid-1 (TRPV1) channels abound in corneal nerve fibers and respond to inflammation-derived ligands, which increase in DED. TRPV1 overactivation promotes axonal degeneration in vitro but whether it participates in DED-associated corneal nerve dysfunction is unknown. To explore this, DED was surgically induced in wild-type and TRPV1-knockout (Trpv1KO) mice, which developed comparable corneal epithelial damage and reduced tear secretion...

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease for which there is no curative therapy available. Repetitive alveolar epithelial injury repair, myofibroblast (MYF) accumulation and excessive collagen deposition are key pathological features of IPF, eventually leading to cellular hypoxia and respiratory failure. The precise mechanism driving this complex maladaptive process remains inadequately understood. WSB1 (WD repeat and SOCS box containing 1) is an E3 ubiquitin ligase, the expression of which is strongly associated with hypoxia, and forms a positive feedback loop with HIF-1α under anoxic condition...

Isocitrate dehydrogenase gene (IDH) mutation is one of the most important molecular markers of glioma. Accurate detection of IDH status is a crucial step for integrated diagnosis of adult-type diffuse gliomas. A clustering-based hybrid of a convolutional neural network and a vision transformer deep learning model was developed to detect IDH mutation status from annotation-free hematoxylin and eosin-stained whole slide pathologic images of 2275 adult patients with diffuse gliomas. For comparison, we also assessed a pure convolutional neural network, a pure vision transformer, and a classic multiple-instance learning model...